rs61749721

Variant names:

• chrX-154031065-G-A
• rs61749721
• NM_001110792.2:c.799C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031065-G-A
• chrX-154031065-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.799C>T​(p.Arg267*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000282496: Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R267R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:49 O:1
• Conservation: PhyloP100: 2.35
• Publications: 257 publications found

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 427 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000282496: Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes.; SCV001984846: Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114).; SCV004100344: Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression Yusufzai and Wolffe, 2000; Delépine et al., 2013.; SCV005088883: "In-vitro functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression." PMID:23238081, 11058114; SCV000191046: Functional studies indicate this variant affects the protein's ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013);; SCV000604145: Functional studies showed p.Arg255Ter to be less stable in vivo and lead to deficient transcriptional repression (Yusufzai 2000).; SCV003920190: "In addition, functional studies have shown a deleterious effect of this variant (Yusufzai 2000 PMID:11058114, Delepine 2013 PMID:23238081, Pitcher 2015 PMID:25634563)."; SCV000645677: Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081, 25634563).; SCV004046073: Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031065-G-A is Pathogenic according to our data. Variant chrX-154031065-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.799C>T	p.Arg267*	stop_gained	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.763C>T	p.Arg255*	stop_gained	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.484C>T	p.Arg162*	stop_gained	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.799C>T	p.Arg267*	stop_gained	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.763C>T	p.Arg255*	stop_gained	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.763C>T	p.Arg255*	stop_gained	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000396 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
23	-	-	Rett syndrome (24)
14	-	-	not provided (14)
3	-	-	MECP2-related disorder (3)
2	-	-	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (2)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Autism (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	Severe neonatal-onset encephalopathy with microcephaly (1)
1	-	-	Syndromic X-linked intellectual disability Lubs type (1)
1	-	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.43	T
MetaRNN	Pathogenic	0.84	D
PhyloP100		2.4
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61749721; hg19: chrX-153296516; COSMIC: COSV100317851; COSMIC: COSV100317851;